Regenerative Medicine

Regenerative Medicine for Nervous System and Heart (by Shaunak Raole)

This branch of medicine involves replacing, engineering, or regenerating human or animal cells, tissues or organs for restoring or establishing normal control. This is mainly done by stimulating the body’s intrinsic mechanisms. Another part of regenerative medicine is growing tissues and organs in the laboratory and then implanting them into the body when it can’t heal itself. If the patient’s own tissue/cells are used for deriving the cell source for the regenerated organ, immunological transplant rejection can be overcome. As donor organs can lead to an immune response and are hard to obtain, Artificial Organs become a viable alternative. Tissue Engineering involves implanting structures called scaffolds in the body which act as skeletons for cells to grow upon and form tissues. Regenerative medicine also deals with using stem cells. This comes under cell therapy. Stem cells can be utilized for self-repair, by injecting them into the damaged site, leading to tissue rebuilding. Bone Marrow, skeletal muscle, etc are some of the many sources of stem cells.

Regenerative Medicine for Nervous System (Stem Cell Therapy)

Currently it is well known that neural progenitor/stem cells are present in the neurogenic niches (in the adult human brain), and two such major neurogenic niches have been identified; at the subgranular zone within the dentate gyrus of the hippocampus, and one at the subventricular zone, lining the lateral ventricles. The Adult subventricular zone neural progenitor/ stem cells are also called Type B cells and are responsible for giving rise to transient amplifying progenitors (C-cells), which then divide and become neuroblasts (A-cells). A-cells differentiate into further sub-types of interneurons. Type 1 cells, which are the radial glia-like neural stem cells, give rise to intermediate progenitor cells and neuroblasts further differentiating into dentate granule neurons [1,2]. 

The adult somatic neural stem cells have a homeostatic role in functional brain repair after injury and provide plasticity to the neuronal circuit. This is via the addition of immature new neurons with properties like hyperexcitability and by making new synaptic contacts with mature neurons. [3]

Stem cell therapy for Cerebral Palsy:

In a study it was seen that when patients suffering from cerebral palsy were treated with autologous bone marrow mononuclear stem cells, the gross motor and fine motor functions were improved within 3 to 6 months after the therapy and were found to be safe [4]. Another group of researchers found that umbilical cord-derived mesenchymal stromal cells bettered the motor functions of a pair of twins suffering from cerebral palsy [5].

Stem cell therapy for Stroke:

Strokes occur when there is a blockage of blood supply to the brain. It has been seen that stem cell therapy using mesenchymal cells can be used to repair resulting brain damage. Studies done in-vivo (in animal models with ischemic stroke) have shown that stroke stem cell treatment has allowed functional recovery, indicating that mesenchymal stem cells can promote repair. Along with this, mononuclear fraction generation consisting of numerous cells which secrete cytokines and trophic factors is seen. This helps towards the generation of blood supply, neuroprotection, and neuro-regeneration in stroke-affected areas. The advantage of stroke stem cell therapy is that the mesenchymal stem cell transplants don’t involve invasive operations, and no ethical issues are involved.

 

Image Credits:

https://www.neurogenbsi.com/stem-cell-treatment-for-stroke-patients

The left image shows a PET CT scan of stroke afflicted 68-year-old man and is of pre-cell therapy. The green area indicates normal metabolism, blue is a penumbral area (the area around the stroke showing hypometabolism), and the black area is the gliotic area, which is the main stroke area. The right image is of the post cell therapy PET CT scan, and it is seen that the green area has increased, and the blue area has decreased, which indicates that the metabolism is increased in the area affected by the stroke. [6]

Stem Cell Therapy for Alzheimer’s disease

AD is a progressive neurodegenerative disease where the patient suffers from memory loss and cognitive impairment, caused by synaptic failure and excessive accumulation of misfolded proteins. Stem cell treatment has been found to be useful in AD animal models, with promising pre-clinical studies.

1.     Neural Stem Cells: In a study by Sinden et al, it was found that when choline-rich neural stem cells were transplanted, AD symptoms were found to be reduced [7]. Another study involved using genetically engineered NSCs, which stably released Aβ-degrading enzyme neprilysin, and it was seen that synaptic plasticity was enhanced and the pathological characteristics of the transgenic mice were improved. [8]

2.     Mesenchymal Stem Cells: They provide three main roles in AD treatment: Immune regulation, reduction of Abeta plaque, and neurotrophic/regenerative potential. In a study, it was seen that fluorescent protein labelled bone marrow MSCs reduced the size of Abeta plaques in the hippocampus of animal models. [9]

3.     Induced Pluripotent Stem Cells: iPSCs have been shown to regulate endogenous neurogenesis, replace lost neurons, or reverse pathological changes. A study showed that protein-induced iPSCs reduced plaque deposition and improved bilateral brain transplantation in transgenic mice with AD [10].

Regenerative Medicine for Heart

Heart failure can occur during myocardial infarction due to loss of cardiomyocytes. Sadly, the heart has a very poor regenerative capacity, mainly due to the hostile environment created in the myocardium after myocardial infarction.

Stem Cell Therapy:

One of the best ways to form new contractile tissue is stem cell therapy. There are several types of adult stem cells  that have been utilized for treating patients with acute myocardial infarction and heart failure.

1.     Skeletal Myoblasts: They are progenitor cells located between basal lamina and sarcolemma, and get activated in response to damage to the muscle or disease-induced muscle degeneration. Once activated they express Myf-5 and/or MyoD. They have a high proliferative potential in-vivo. Clinical studies have shown that they can reduce the left ventricular re-modelling and interstitial fibrosis, and also provide improved systolic and diastolic benefits. [11]

2.     Bone Marrow-Derived Cells: They have been used to treat myocardial infarction and heart failure for many years. A preclinical study showed that when injected in-vivo, the bone marrow cells were able to regenerate the infarcted myocardium and improve cardiac function. [12]

3.     Induced Pluripotent Stem Cells: iPSCs are derived from somatic cells and then subsequently differentiated into many kinds of cells in our body. iPSCs generated for cardiovascular research displayed the capacity to differentiate into function cardiomyocytes [13]. A group of researchers demonstrated fibroblast re-programming by using stemness factors like OCT3/4, SOX2, KLF4, and c-MYC, and once the transformed cells were transplanted, an improvement in contractile performance, electrical stability, and ventricular wall thickness was seen due to regeneration of cardiac muscle along with smooth muscle and endothelial tissues [14].

Tissue Engineering for the Heart

While not absolutely applied for routine clinical applications, stem cell transplants for cardiac therapies have been successful as seen in some clinical trials, which also shows the promise for tissue engineering.

Human engineered cardiac tissues (hECTs) are good examples. They are derived from experimental manipulation of pluripotent stems cells like hESCs, and recently, from human induced pluripotent stem cells (hiPSCs) for differentiating into human cardiomyocytes. They have shown therapeutic potential for generating heart muscles in-vivo, and can also be used for engineered tissue-based therapies for CVD patients. Three dimensions scaffolds are used along with collagen which, being a major component of the cardiac extracellular matrix, helps mimic the microenvironment and provided biocompatibility for promoting cardiomyocyte organization, growth and differentiation [15]. Along with this, ML and evolutionary algorithms have been employed for stemness features dealing with local microenvironment changes, 3D scaffolds, etc. [16]

CRISPR/Cas systems have also been used for reactivating non-dividing cells as well as terminally differentiated mammalian cells, or to change the cell structures when needed, for addressing tissue architecture formation. These both have been demonstrated for cardiac stem cell engineering. CRISPR/Cas9 can also be used to edit the iPSCs-derived CMs in situ, which can readily differentiate into transplantable cells. [16]

Lastly, GRNs (Gene Regulatory Networks) can play a part in the spatiotemporal expression of desired cardiac regeneration-related proteins. The products can be involved in many endogenous and exogenous physio-chemical stimuli, for producing growth factors or cytokines which help shape the cardiac tissue structure. Many challenges of tissue regeneration can be overcome by regulating GRN via using techniques of Synthetic Biology and Bioinformatics. [16]

By Shaunak Raole

https://replicoo.blogspot.com/2021/07/retrieving-protein-sequences-and-structure.html

https://replicoo.blogspot.com/2021/07/biochemistry-of-apoptosis.html

https://replicoo.blogspot.com/2021/07/immunotherapy-for-cancer.html

References:

1. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–716.

2. Berg DA, Bond AM, Ming GL, Song H. Radial glial cells in the adult dentate gyrus: what are they and where do they come from? F1000Res. 2018;7:277.

3. Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70:687–702.

4. Nguyen LT, Nguyen AT, Vu CD, Ngo DV, Bui AV. Outcomes of autologous bone marrow mononuclear cells for cerebral palsy: an open label uncontrolled clinical trial. BMC Pediatr. 2017;17:104.

5. Kang M, Min K, Jang J, et al. Involvement of immune responses in the efficacy of cord blood cell therapy for cerebral palsy. Stem Cells Dev. 2015;24:2259–2268.

6. https://www.neurogenbsi.com/stem-cell-treatment-for-stroke-patients

7. Functional repair with neural stem cells Sinden JD, Stroemer P, Grigoryan G, Patel S, French SJ, Hodges H Novartis Found Symp. 2000; 231():270-83; discussion 283-8, 302-6

8. Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models.Blurton-Jones M, Spencer B, Michael S, Castello NA, Agazaryan AA, Davis JL, Müller FJ, Loring JF, Masliah E, LaFerla FM Stem Cell Res Ther. 2014 Apr 16; 5(2):46.

9. Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Naaldijk Y, Jäger C, Fabian C, Leovsky C, Blüher A, Rudolph L, Hinze A, Stolzing A Neuropathol Appl Neurobiol. 2017 Jun; 43(4):299-314.

10. Protein-Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Aβ Deposition in a Mouse Model of Alzheimer's Disease. Cha MY, Kwon YW, Ahn HS, Jeong H, Lee YY, Moon M, Baik SH, Kim DK, Song H, Yi EC, Hwang D, Kim HS, Mook-Jung I Stem Cells Transl Med. 2017 Jan; 6(1):293-305.

11. Hagege AA, Marolleau JP, Vilquin JT, et al. Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients. Circulation. 2006;114:I108–I113.

12. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999;100:Ii247–Ii256.

13. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30–e41.

14. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A. Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation. 2009;120:408–416.

15. Tulloch NL, Murry CE. Trends in cardiovascular engineering: organizing the human heart. Trends Cardiovasc Med. 2013 Nov;23(8):282-6. doi: 10.1016/j.tcm.2013.04.001. Epub 2013 May 27. PMID: 23722092; PMCID: PMC3791174

16. Nguyen, A.H., Marsh, P., Schmiess-Heine, L. et al. Cardiac tissue engineering: state-of-the-art methods and outlook. J Biol Eng 13, 57 (2019). https://doi.org/10.1186/s13036-019-0185-0